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In older women, brief suspensions of respiration during sleep (apnea) may cause more than daytime drowsiness, increased cardiovascular risk, and insulin resistance—it may also lead to mild cognitive impairment (MCI) or dementia. Results published in last week’s Journal of the American Medical Association showed that women with sleep-disordered breathing (SDB)—pauses in breathing or reduced ventilation quality during sleep—are more likely to develop cognitive impairment five years later. Hypoxia seems to be the culprit, the authors concluded.

"Given the high prevalence of both sleep-disordered breathing and cognitive impairment among older adults, the possibility of an association between the two conditions, even a modest one, has the potential for a large public health impact," wrote the authors led by Kristine Yaffe of the University of California, San Francisco, and Katie Stone of the California Pacific Medical Center Research Institute in San Francisco.

The researchers longitudinally observed a subset of women enrolled in the large Study of Osteoporotic Fractures—a multicenter analysis of more than 10,000 community-dwelling women. First author Yaffe and colleagues wanted to see if older women with SDB had a higher chance of developing MCI or dementia. Previous cross-sectional studies were conflicted about the link, and no one had done a prospective study to see if older, dementia-free individuals with SDB later developed cognitive problems.

Between 2002 and 2004, the researchers conducted behavioral tests—including the Mini-Mental State Examination and a modified version of Trails B—and an at-home sleep study of 461 women (mean age 82.3 years) from Minneapolis, Minnesota, and the Monongahela Valley, near Pittsburgh, Pennsylvania. None of these women had dementia at baseline, or used SDB therapy, such as continuous positive airway pressure (CPAP) devices or supplemental oxygen therapy. During sleep testing, a team overseen by Susan Redline of Harvard Medical School measured variables such as the number of arousals per hour and the number of airflow cessations (apnea) or reductions (hypopnea) lasting 10 seconds or longer with an associated dip in blood oxygen saturation of 3 percent or more per hour. Among the 298 women who met the criteria for inclusion in the final sample, 35.2 percent were classified as having SDB.

At the time of follow-up about five years later, the women underwent more extensive cognitive tests than they did at baseline. Of the women who did not have SDB at baseline, 31.1 developed MCI or dementia. Of the women who did have SDB, 44.8 percent received one of the diagnoses. After adjusting for demographic and physiological factors, as well as disease and medication use, the researchers found that the odds of developing MCI or dementia were 85 percent higher for women with SDB. Adjusting for baseline cognitive test scores increased the odds ratio to 2.36.

"This suggests that women who have sleep-disordered breathing are at greater risk of subsequent cognitive impairment," said coauthor Adam Spira of The Johns Hopkins Bloomberg School of Public Health in Baltimore, Maryland. "It's possible that there is a causal link there."

Intermittent oxygen deprivation could be responsible, the authors suggested. Increased hypoxia—a higher percentage of total sleep time in hypopnea or apnea and greater oxygen desaturations per hour, rather than total sleep time or sleep fragmentation—was associated with MCI or dementia. If that's the case, CPAP or supplemental oxygen therapy could mitigate sleep apnea's harmful effects, the authors wrote. "No medications are known to prevent the progression of mild cognitive impairment to Alzheimer's disease or dementia, so treating at-risk patients with CPAP for sleep-disordered breathing is a prevention strategy that may be worth testing," wrote Nicola Canessa and Luigi Ferini-Strambi of the San Raffaele Scientific Institute in Milan, Italy, in an accompanying JAMA editorial.

For patients whose apnea results from venous insufficiency, a recent paper suggests that compression stockings can decrease nightly apneas and hypopneas by reducing the daily accumulation of fluid in the legs that redistributes in the neck during sleep. Researchers led by Stefania Redolfi published their results online last week in the American Journal for Respiratory Care and Critical Medicine.

Yaffe's study "does indicate that certain populations might be more severely affected by sleep apnea," said Clete A. Kushida, medical director of the Stanford Sleep Medicine Center in California. Kushida directs the NIH-sponsored Apnea Positive Pressure Long-Term Efficacy Study (APPLES), which aims to determine the effects of CPAP therapy on neurocognitive function. So far, the study has found that the severity of apnea in middle-aged adults is mildly associated with worsened neurocognitive performance (see Quan et al., 2011).

Previous research has shown that CPAP treatment slows or improves cognitive impairment in patients with Alzheimer's disease (see Ancoli-Israel et al., 2008 and Cooke et al., 2009), and increases gray matter volume in the hippocampus and frontal area (see Canessa et al., 2011). And other studies have pointed to a role for hypoxia in amyloid-β deposition. In cultured cells and mouse AD models, hypoxia increases the expression and activity of the APP-processing enzyme β-secretase (BACE1), which cleaves APP to generate the amyloid-β peptide that deposits in the brain (see ARF related news story on Sun et al., 2006). The hypoxia inducible factor 1α binds to the BACE1 promoter and increases the BACE1 mRNA and protein levels (see ARF related news story on Mehta et al. 2009 and Zhang et al., 2007).

But further research is needed to establish causation, as Yaffe and colleagues point out in their paper. Randomized control trials with larger sample sizes that include men and more ethnically diverse participants could test whether CPAP or supplemental oxygen therapy prevents cognitive decline. "Also, it would be helpful to determine what brain pathology is associated with the dementia developed by older women with sleep-disordered breathing compared to older women without," said Raj C. Shah, assistant professor at the Rush University Medical Center in Chicago, Illinois. "It could be that sleep-disordered breathing is more likely to be linked to [brain] infarcts rather that AD pathology." Brain infarcts, or mini-strokes, are more common in those with sleep-disordered breathing (see Minoguchi et al., 2007), and increased white matter hyperintensities (a measure of those strokes) have been linked to dementia (see Carmichael et al., 2010).—Gwyneth Dickey Zakaib

Comments on News and Primary Papers

This study by Yaffe, et al. provides a new avenue of investigation into a potentially modifiable risk factor for developing mild cognitive impairment (MCI) or dementia. The study is the first to show a temporal relationship where sleep-disordered breathing with hypoxia seems to occur before the onset of MCI or dementia. However, further work will be needed to confirm the temporal, cause-effect relationship prior to suggesting clinical interventions for sleep-disordered breathing with hypoxia as a prevention for dementia. The pathology changes in the brain (amyloid plaques, tangles, infarcts, and Lewy bodies) seem to build up for decades during the cognitively asymptomatic phase of dementia. Therefore, the study findings may be explained by brain pathology affecting the central brain pathways for regulating respiration in sleep earlier than affecting pathways associated with cognition. Also, it would be helpful to determine what brain pathology is associated with the dementia older women with sleep-disordered breathing developed as compared to older women without sleep-disordered breathing with hypoxia. It could be that sleep-disordered breathing is more likely to be linked to infarcts rather that AD pathology. Infarcts have been shown to accelerate the manifestation of dementia symptoms. Again, this paper is an important contribution to our understanding of dementia and opens up novel avenues for further exploration.

This is an important and provocative observational study. The notion that sleep apnea could be associated with cognitive impairment has been documented in the scientific literature for over 25 years; what this study does, somewhat uniquely, is demonstrate that in an elderly community population, sleep apnea may lead unambiguously to progressive decline in cognition over time. However, the implications of the study for treatment remain uncertain (as would be the case for any observational study).

Unresolved issues for treatment would be: 1) At what point to initiate treatment? 2) How long would it take to see a response? 3) What kind of treatment would one undertake? 4) (related to #1 and #2) What would constitute a response?

To place this all in context, there can be no doubt that treating cognitively impaired, elderly patients' hypertension, cardiac insufficiency, or diabetes would help their overall physical function and might improve some elements of cognition as well, but to infer that acute treatment of such conditions would cure dementia would be misleading. On the other hand, by attending to health issues such as these (and this would include sleep apnea) over the long term (i.e., from middle age on through old age), one is likely to reduce that burden of medical disease on higher brain function and could very well prevent (or at least forestall) the onset for impaired cognition in late life.

This report should be supported by the pathogenic confirmation of Alzheimer’s disease, but it is still a very attractive observation for the Alzheimer’s field. Currently, it is popular to clarify the pathogenic mechanisms that induce MCI or early Alzheimer’s dementia, and this paper has opened a new window on MCI. It is well known that hypoxia generates oxygen radicals, which have harmful effects on neuronal function. Hypoxia has recently been linked to MCI and dementia.

We recently found that homocysteic acid (HA) is a possible risk factor for AD, and that it may be linked to hypoxia (1).

We observed that cystathionine β-synthase (CBS) can produce HA via homocysteine and oxygen radicals, and that HA might affect the hippocampus to cause memory impairment in transgenic mice (2). That the same might happen in humans may be tested by the detection of blood HA in MCI patients. We are working on this now.

Finally, older women who suffer from sleep hypoxia may benefit from antioxidants, which suppress oxygen radicals.